Aerosol type dispensers are used throughout the world for dispensing a wide range of products, for example hair lacquer, furniture polish, cleaners, paint, insect killers and medicaments.
Liquefied compressed gases are invariably used as the propellant for aerosol dispensers for inhalation therapy in preference to non-liquefied compressed gasses such as nitrogen or carbon dioxide, as they confer the following critical advantages:
a) the spray undergoes flash evaporation to give aerosols of very small particle size PA1 b) the spray particle size remains constant during pack emptying as the inhaler vapour pressure is maintained at an almost constant level by progressive propellant evaporation PA1 c) the pressure generated by partial evaporation of propellant in the valve metering chamber causes efficient discharging of the metered valve contents and accurate dose delivery PA1 d) suitably designed formulations have notably good chemical drug stability and resistance to microbial growth.
FIGS. 1A and 1B of the accompanying drawings show the valve and lower portion of a typical MDI aerosol dispenser in closed and open positions respectively. Such dispensers generally comprise a small aluminium shuttle valve 1 which is crimp fitted to the can 2 containing the drug and chlorofluorocarbon (CFC) propellants. The valve is activated by manually pressing shuttle pin 3 such that it moves a small distance into the can 2. In order to do this it is necessary to overcome the force exerted on the pin 3 by virtue spring 4 and of the pressure within the container. Pressures within such dispensers are typically around 8 bar which is sufficient to maintain CFC propellants in a liquid state at ambient temperatures.
Until recently, CFCs were the most common of the propellant gases used in aerosols because they are inert, miscible with a wide range of products, are easily liquefied under low pressures, give a substantially constant product flow-rate, and can produce sprays of droplets having mean diameters in the range of 3 to over 100 micrometers. However, in the 1970's it was proposed that CFCs were probably responsible for depleting the Earth's protective ozone layer, and in 1987, most countries signed the Montreal Protocol to phase out the use of CFCs and have since agreed to stop use of CFCs for non-essential applications by the end of 1995. One notable exemption to this deadline for cessation of use is in relation to MDIs for medicaments, which are regarded as an essential use of CFCs, but even this use of CFCs will be phased out as acceptable alternatives are developed.
Many companies are now working to develop alternative CFC--free propellants for use in aerosol spray devices including MDIs to overcome the ozone destructing properties of conventional CFC containing propellants. A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional CFCs comprise fluorocarbons and hydrogen-containing fluorocarbons (commonly known as HFA propellants), and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example European Patent Application Publication No. 0372777 and PCT Patent Application Nos. WO91/04011 WO91/11173, WO91/11495 and WO91/14422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared. The applications all propose the addition of one or more of adjuvents such as alcohols, alkanes, dimethyl ether, surfactants and even conventional chlorofluorocarbon propellants in small amounts to minimise potential ozone damage. Surfactants are added to make the suspension formulations stable. However, whilst surfactants may conveniently be used in MDIs which use CFC propellants, surfactants are not generally solvent in HFA propellants and so require the use of additional co-solvents.
Attempts have also been made to develop devices which produce satisfactory spray characteristics making use of compressed gases such as nitrogen and carbon dioxide, which are present in the atmosphere in relatively large proportions. The main problem associated with aerosol dispensers of this type which use compressed gas propellant is that whilst the spray characteristics may be satisfactory when the dispenser is full and the propellant is at a high pressure, they display a serious drop in pressure during emptying as the available headspace increases with the result that the atomizing and spray pattern deteriorate to an extent that dispensing becomes unsatisfactory for many purposes. Such dispensers may be used where such deterioration of the atomization and spray pattern are of no concern, e.g. in the dispensing of foodstuffs, but it has not been found to be useful in areas where atomization and spray patterns are important, e.g. in dispensing of medicaments. For this latter application it is often required to deliver drugs to topically treat the lung or to provide a route for absorption into the blood stream of drugs that are poorly absorbed from the alimentary tract. To reach the alveoli it is essential that the aerodynamic size of the particles is less than 10 micrometers, preferably between 0.5 and 5 micrometers. In order to reliably reproduce aerosol sprays from a dispenser in which the majority of particles have a size of between 0.5 and 5 micrometers it is necessary to maintain a fairly constant propellant pressure.
The pressures that would be required to maintain gases such as carbon dioxide in a liquid state at ambient temperatures are typically of the order of 10 times greater than that within a conventional dispenser such as that shown in FIGS. 1A and 1B, and such pressures are far in excess of those within any dispensers currently available. Hence to maintain the same activation force, the shuttle pin diameter would need to be reduced accordingly resulting in more stringent engineering requirements.
U.S. Pat. No. 5,301,664 describes an apparatus for producing a gas-borne dispersion of a physiologically active solute dissolved in a supercritical fluid solvent. The supercritical fluid solution is passed into a subcritical region to evaporate the solvent and form an aerosol cloud of the solute particles. Some of the problems associated with this device are that: (i) the temperature and pressure of the reservoir must be maintained above the critical temperature and pressure of the solvent in order to maintain supercritical conditions, and (ii) to ensure consistent delivery of solute dose upon each actuation of the valve it is necessary to either reduce the reservoir volume each time a dose is delivered by the magnitude of the volume dispensed to maintain solute density, or increase the dose size accordingly.
European Patent Application 675054 (published after the priority date of this application) describes a constant quantity injection valve and canister for carbon dioxide however it does not discuss the use of solutions or suspensions of substances in carbon dioxide, nor does it mention use of the valve in an apparatus for inhalation therapy. Furthermore, since opening of the valve requires the pressure inside the canister to be overcome, the arrangement is disadvantageous when the carbon dioxide is under very high pressure.
European Patent Application 677332 (published after the priority date of this application) describes a method and apparatus for producing fine particles of substance which comprises dissolving the substance in a first liquid, mixing the resultant solution with a second fluid (such as supercritical carbon dioxide) and then rapidly lowering the pressure. However this method may not be suitable for all substances and the apparatus is relatively complex since it requires control of a mixing step. Furthermore, if the solvent of the first liquid is itself soluble in the second fluid, the dissolved substance may start to recrystallise in an uncontrolled manner prior to the pressure being lowered.